New therapy uses a pancreatic hormone as a trojan horse
'Smart drug' clears fat from liver and blood
The constant rise in obesity and diabetes represents a major burden to modern societies. Fatty liver and atherosclerosis are frequent consequences of these metabolic diseases. An efficient and safe medicine, which would reverse obesity, insulin resistance, fatty liver and atherosclerosis remains a major scientific challenge of global priority. An international team led by metabolism experts Professor Matthias Tschöp, Chair of Metabolic Diseases at TUM and director of the Institute for Diabetes at Helmholtz Zentrum München, Richard diMarchi (Indiana University) and Timo Müller (Helmholtz Zentrum München) report in the current issue of ‘Cell’ that liver-specific delivery of the thyroid hormone T3 using glucagon corrects obesity, glucose intolerance, fatty liver disease and atherosclerosis without causing adverse effects in other tissues. “While the ability of T3 to lower cholesterol is known for centuries, deleterious effects, in particular on the skeleton and the cardiovascular system, do so far limit its medicinal utility”, says Brian Finan, the first author of the manuscript.
Toward precision medicines of the future
“Part of our trick is, that we use the pancreatic hormone glucagon as a vehicle to deliver thyroid hormone only into cells carrying a glucagon receptor”, says Christoffer Clemmensen, who led several of the key experiments. He explains: “Since there are lots of glucagon receptors in the liver, but almost none in heart or bone, our molecule concentrates thyroid hormone action to the liver while keeping it away from places where it would be harmful”.
The newly developed glucagon/T3 molecule delivered the T3 selectively to the liver and thereby safely improved within a few days cholesterol metabolism in diet-induced obese mice. The molecule further decreased body weight, corrected non-alcoholic fatty liver disease, and improved glucose metabolism without deleterious effects of T3 in the heart and bone. Notably, the molecule failed to improve metabolism in mice lacking either the glucagon receptor or which lack the thyroid hormone receptor in only the liver, demonstrating the liver-specific signal specificity of this new molecule.
“The next task is to see whether this drug candidate will reach the same level of targeted tissue-selectivity in clinical studies”, says diMarchi. “If the molecule shows equal efficacy and safety in humans, then this particular ‘smart’ drug design may indeed offer perspectives for metabolic precision medicine”, summarizes Tschöp.
Original publication
Finan, B.& Clemmensen, C. et al. (2016): Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease. Cell, DOI: 10.1016/j.cell.2016.09.014
Contact
Dr. Timo Müller
Helmholtz Zentrum München
Tel. +49 89 3187 2106
timo.mueller@helmholtz-muenchen.de